New methods in genomics and chemistry technologies hold tremendous promise for impact on the process by which drugs are developed. Such impact, however, has yet to be realized, as these emerging methods have yet to be integrated into a discovery effort. Furthermore, the capabilities themselves need to be further developed before they can be used routinely in the drug discovery process. We therefore propose here to bring these capabilities together to create a new paradigm for drug discovery that integrates the disciplines of synthetic organic chemistry, cell biology, genomics and information science. While there is much activity in these individual areas, never before have they been synthesized and focused in such a way as to> create a new conceptual framework for drug discovery. The goal of this component of the overall Broad IRC program is therefore to create the capabilities necessary for an integrated 'pipeline' that can be applied to a wide range of applications and can be readily adopted by many groups in both academia and industry. Specifically, in Aim 1 we will develop new approaches to cell-based high throughput screening based on gene expression signatures and high content imaging. In Aim 2, we will leverage the power of Diversity Oriented Synthesis (DOS) to create powerful small molecule libraries suitable for screening and subsequent optimization. In Aim 3, we will develop novel strategies for toxicogenomics with the goal of using this information to better prioritize lead compounds for subsequent testing in vivo.